Despite progress in developing new approaches to therapy of lymphoma, including use of monoclonal antibodies (moAbs), our understanding of the mechanisms responsible for the efficacy of these treatments remains incomplete. Much of what we understand comes from the in vitro analysis of cell lines or lymphoma cells from patients, or evaluation of therapy in murine models. This information has been extremely valuable, however the resulting data often does not reflect what is happening in vivo in patients. In recent years, there has also been significant progress in functional imaging techniques that are allowing us to image biochemical and cellular processes in vivo in patients. A number of functional imaging tools should also be useful in evaluating the cellular and molecular changes that occur in vivo in patients following anti- lymphoma therapy including both moAb therapy and chemotherapy. Three mechanisms of action that are attracting considerable attention are antibody dependent cellular cytotoxicity, apoptosis, and inhibition of proliferation. The current project was designed to help us begin the process of applying in vivo function imaging tools to explore the mechanisms responsible for the anti-lymphoma effects of therapy. In aim #1, we will evaluate trafficking of radiolabeled mononuclear and polymorphonuclear leukocytes into tumor prior to and after moAb therapy to assess whether binding of moAb to lymphoma cells within nodes leads to a series of events that results in trafficking of effector cells to the involved nodes. In aim #2 we will use 99mTc-labeled Annexin V (Apromate) to assess the feasibility of imaging treatment-induced apoptosis in patients with aggressive NHL leading anthracycline-based chemotherapy. In aim #3 we will determine whether correlation exists between thymidine uptake in tumor using FLT-PET and in vitro assays such as BrdUrd labeling index and % S-phase. These tools could prove extremely valuable as we seek to understand the mechanism of action of a variety of treatments including chemotherapy and moAb therapy, and work to find surrogate markers that will be useful in the design of even more effective approaches to therapy.